tbuckley/cabot-search huggingface dataset:
Abstract 4223: Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform
Authors: Jean-Philippe Carralot, Matilde Arévalo Ruiz, Robert Tam, Eric Armentani, Vijaya R. Pattabiraman, Bertolt Kreft
Journal: Cancer Research (2022)

Abstract Immunocytokines (IC) provide the opportunity for targeted delivery of cytokines as payloads to tissues and cells to improve safety and efficacy of cytokine-based therapies. ICs have gained significant interest in recent years and several antibody-cytokine fusion proteins have entered clinical trials. Compared to recombinant fusion proteins, we have developed an entirely different approach to IC generation based on the site-specific, chemical conjugation of synthetic cytokines to antibodies. Bright Peak generates enhanced and conjugatable cytokines using a novel protein engineering platform based on solid-phase peptide synthesis and subsequent chemical ligation of protein segments. Our synthetic cytokines can then be readily chemically conjugated to specific lysine residues in the Fc region of an existing IgG1, IgG2 or IgG4 antibody without the need for prior antibody engineering. Chemical conjugation of cytokine payloads is rapid, enabling the flexible generation of ICs based on different antibodies and payloads within weeks. We applied our technology to more than 10 antibodies and found that neither antigen binding nor payload potency and selectivity are affected by chemical conjugation. Importantly, binding of the Fc domain of ICs to Fc gamma receptors or FcRn is not significantly affected. We are initially focusing on the development of PD-1-targeted ICs to achieve dual-targeting of PD-1+ effector T cells (cis-signaling). Using several anti-PD-1 antibodies and various synthetic IL-2 variants as payloads, we created ICs with different drug-antibody ratios and explored alternative conjugation sites within the Fc region. Resulting PD-1/IL-2 ICs are highly active showing significantly enhanced potency due to avidity resulting from binding of the cytokine to PD-1+ effector T cells in cis. Our PD-1/IL-2 ICs induce strong pharmacodynamic effects in vivo, and we are currently optimizing the pharmacological profiles of PD-1-targeted ICs for clinical application. In addition, we are actively exploring cis-signaling ICs targeting different surface receptors and immune cells. Citation Format: Jean-Philippe Carralot, Matilde Arévalo Ruiz, Robert Tam, Eric Armentani, Vijaya R. Pattabiraman, Bertolt Kreft. Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4223.
Genome-wide polygenic score to predict chronic kidney disease across ancestries
Authors: Atlas Khan, Michael C. Turchin, Amit Patki, Vinodh Srinivasasainagendra, Ning Shang, Rajiv Nadukuru, Alana C. Jones, Edyta Malolepsza, Ozan Dikilitas, Iftikhar J. Kullo, Daniel J. Schaid, Elizabeth Karlson, Tian Ge, James B. Meigs, Jordan W. Smoller, Christoph Lange, David R. Crosslin, Gail P. Jarvik, Pavan K. Bhatraju, Jacklyn N. Hellwege, Paulette Chandler, Laura Rasmussen Torvik, Alex Fedotov, Cong Liu, Christopher Kachulis, Niall Lennon, Noura S. Abul-Husn, Judy H. Cho, Iuliana Ionita-Laza, Ali G. Gharavi, Wendy K. Chung, George Hripcsak, Chunhua Weng, Girish Nadkarni, Marguerite R. Irvin, Hemant K. Tiwari, Eimear E. Kenny, Nita A. Limdi, Krzysztof Kiryluk
Journal: Nature Medicine (2022)
Abstract 3875: <i>De novo</i> spatial proteomic profiling of immune synapses using machine learning-guided microscoop
Authors: You-Pi Liu, Weng Man Chong, Harry Huang, Yi-De Chen, Chia-Wen Chung, Hsiao-Jen Chang, Chih-Wei Chang, Jung-Chi Liao
Journal: Cancer Research (2022)

Abstract The spatial proteome of the immune synapse (IS) between a target cell and a lymphocyte is fundamentally important to understand the mechanism of cell-mediated immunity for both immuno-oncology and therapeutic applications. In this research, we used Microscoop, a fully-automatic microscope system integrated with a machine learning-based algorithm, to best determine ISs for proteomic mapping. We used Raji B cells as antigen-presenting cells (APCs) and induced the formation of ISs by incubating with Jurkat T cells. Multiple IS images were applied to train our algorithm using convolution neural network-based deep learning. A sequential process including fluorescence imaging, deep learning-enabled pattern generation, and photochemical labeling was implemented to achieve spatial-specific biotinylation of the IS proteins. Moreover, Microscoop is capable to repeat the process automatically on thousands of fields of view to label sufficient immune-synaptic proteins with biotin-tag for further enrichment allowing protein identification with mass spectrometry. We have successfully labeled and isolated proteins from spatially reorganized interfaces between T cells and APCs. Following MS-based proteomic analysis, several hundreds of proteins were identified, including the proteins known to be specifically associated with T-cell receptor (TCR) activation such as LCK, one of the major factors involved in TCR signaling at ISs. More interestingly, we identified several proteins novel for ISs, including proteins involved in phosphatidylinositol signaling. Our data showcases the capability of subcellular de novo spatial proteomics of the Microscoop technology, revealing novel factors responsible for initiating the immune response of a lymphocyte and shedding light on immune checkpoint signaling and tumor immunotherapy. Citation Format: You-Pi Liu, Weng Man Chong, Harry Huang, Yi-De Chen, Chia-Wen Chung, Hsiao-Jen Chang, Chih-Wei Chang, Jung-Chi Liao. De novo spatial proteomic profiling of immune synapses using machine learning-guided microscoop [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3875.
Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin
Authors: Shijin Hong, Shuai Li, Xiaoyan Meng, Ping Li, Xun Wang, Mengxiang Su, Xiaodong Liu, Li Liu
Journal: Acta Pharmaceutica Sinica B (2022)

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.
Abstract LB018: Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model
Authors: Stella Amanda, Tze King Tan, Jolynn Zu Lin Ong, Madelaine Skolastika Theardy, Regina Wan Ju Wong, Xiao Zi Huang, Muhammad Zulfaqar Ali, Li Yan, Zhiyuan Gong, Hiroshi Inagaki, Ee Yong Foo, Brendan Pang, Soo Yong Tan, Shinsuke Iida, Takaomi Sanda
Journal: Cancer Research (2022)

Abstract IRF4 is a master regulator of immunity and is also frequently overexpressed in mature lymphoid neoplasms. Here, we demonstrate the stage-specific oncogenicity of IRF4 in vivo, its potential effects on T-cell development and clonal evolution using a zebrafish model. IRF4-transgenic zebrafish develop aggressive tumors with massive infiltration of abnormal lymphocytes that spread to distal organs. Many late-stage tumors are mono- or oligoclonal, and tumor cells can expand in recipient animals after transplantation, demonstrating their malignancy. Mutation of p53 significantly accelerates tumor onset, increases penetrance, and results in tumor heterogeneity. Unexpectedly, single-cell RNA-sequencing reveals that majority of tumor cells are double-negative T-cells, many of which express tcr-γ that became dominant as the tumors progress, whereas double-positive T-cells are largely diminished. Gene expression and enhancer profiling demonstrates that gata3, mycb and several genes that were previously not implicated in cancers including lrrn1, patl1 and psip1 are specifically upregulated in tumors, while genes responsible for T-cell differentiation including cxcr4b, id3 and cd8a are repressed. IRF4-driven tumors are sensitive to treatment with the BRD inhibitor (JQ1). Citation Format: Stella Amanda, Tze King Tan, Jolynn Zu Lin Ong, Madelaine Skolastika Theardy, Regina Wan Ju Wong, Xiao Zi Huang, Muhammad Zulfaqar Ali, Li Yan, Zhiyuan Gong, Hiroshi Inagaki, Ee Yong Foo, Brendan Pang, Soo Yong Tan, Shinsuke Iida, Takaomi Sanda. Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB018.
Abstract 5819: Tumor nutrient conditions confer drug resistance in pancreatic cancer
Authors: Colin Sheehan, James Martin, Grace Croley, Joshua McKeever, Anika Thomas-Toth, Patrick Jonker, James LaBelle, Andrew Koh, Alexander Muir
Journal: Cancer Research (2022)

Abstract Drug resistance is a major obstacle to the treatment of pancreatic ductal adenocarcinoma (PDAC). Current standard of care includes combination chemotherapies; however, the majority of patients fail to respond to these treatments. Despite significant advances in our understanding of PDAC biology, it remains unclear what biological processes drives the drug resistance observed in most PDAC cases. Contributing to our limited understanding of this problem, in vitro models of PDAC fail to recapitulate in vivo drug resistance, suggesting the tumor microenvironment is a critical regulator.A defining feature of PDAC tumors is an abnormal nutrient environment, which may carry important biological cues driving many of the undesirable cell behaviors related to disease progression. Using a novel medium formulation that mimics the nutrient conditions observed within PDAC tumors (TIFM), we find that PDAC cells cultured in TIFM become highly resistant to common chemotherapeutic agents, better recapitulating the in vivo drug resistance phenotype than standard cultures. Several of these agents engage with their intended target in TIFM cultured cells, discouraging the idea that drug resistance is primarily mediated by drug efflux. However, TIFM cultured cells display reduced apoptotic priming, enabling their survival to drug exposure. Drug resistance enabled by TIFM nutrients is not immediately reversible with standard culture and can be inherited over multiple cell generations. Consistent with this, we find that TIFM nutrient conditions results in significant alterations to the epigenetic landscape of pancreatic cancer cells, rewiring expression of genes that may function as critical regulators of cell survival in PDAC. Ultimately, the work from this project will help elucidate how poor nutrient perfusion within solid tumors regulates cell survival processes and may lead towards better treatment options for PDAC patients beyond combination chemotherapy. Citation Format: Colin Sheehan, James Martin, Grace Croley, Joshua McKeever, Anika Thomas-Toth, Patrick Jonker, James LaBelle, Andrew Koh, Alexander Muir. Tumor nutrient conditions confer drug resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5819.
Abstract 1026: The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay
Authors: Kang Lin Hsieh, Bor-Sheng Ko, Xiaoqian Jiang, Teng-Jen Chang, Yu-Fen Wang
Journal: Cancer Research (2022)

Abstract Introduction: We studied the association of waiting time from diagnostic Acute Myeloid Leukemia (AML) tests to initial treatment and medical expenditures, length of hospitalization, and survival rates for new AML patients. Method: We extracted 3,976 new AML patients from Optum’s de-identified Clinformatics࣪ Data Mart Database, a data warehouse of adjudicated commercial and medicare advantage claims. Their waiting days from standard diagnostic testings to the initial AML-specific treatment as the risk factor. Medical expenditures occurring within 6 months, 1 year, and 2 years after the index AML diagnosis was measured for the patients’ financial wellbeing, along with the survival rate and the length of hospital stay. We compared these outcomes for patients falling in each waiting time category. Different types of expenditures, including inpatient and outpatient costs for patients with different waiting lengths were compared. Results: For patients with moderate lengths of waiting time, medical expenditure and mortality rate increases and length of hospital stay decreased with waiting time. Within 2 years after the index AML diagnosis, the average expenditures per day goes from $4,803 for patients waiting for 0-2 days to $7,489 for patients waiting for 1-2 weeks, while the survival rate goes from 42.8% to 28.1% and the average length of stay goes from 45.6 days to 35.0 days. The increment in medical expenditure is mostly accounted for by outpatient costs, but is off-set by inpatient costs. The patterns for medical expenditure and survival rate reverse as waiting time becomes severe (3-4 weeks). Similar reverse is not observed for length of stay. Conclusion: The waiting time between AML diagnostic tests and initial treatments is associated with higher medical expenditure and higher mortality rate for moderate waiters. Our findings suggest that reducing waiting time has strong potential in improving AML patients’ survival and financial sustainability. Medical expenditure, survival rate, and length of hospital stay within 2 years by waiting time Medical expenditure per day ($) 2-yr Survival rate (%) Length of hospital stay (days) &amp;lt;2d 4803 42.8 45.6 2-7d 5008 30.3 36.6 7-14d 7489 28.1 33.9 14-28d 4174 29.8 30.4 &amp;gt;28d 2224 51.0 35.0 Citation Format: Kang Lin Hsieh, Bor-Sheng Ko, Xiaoqian Jiang, Teng-Jen Chang, Yu-Fen Wang. The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1026.
Abstract 2153: ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer
Authors: Christopher William Schultz, Yang Zhang, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Devon Atkinson, Liton Saha, Brian Elenbaas, Chien-Fei Lee, Astrid Zimmerman, Thomas Ried, Frank Zenke, Zoe Weaver, Rajaa Elmeskini, Yves Pommier, Anish Thomas
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is a recalcitrant disease with only a 9% five-year survival rate. SCLCs display intertumoral heterogeneity; high neuroendocrine (NE) tumors evolve with treatment and time in a largely MYC driven manner to a chemotherapy resistant non-NE state. Lurbinectedin, an RNA Pol-II inhibitor which causes DNA damage through binding ERCC5 was approved as second line therapy in 2020, with an overall response rate of 35% in patients with relapsed SCLC. However, these responses are short-lived and the majority of patient still succumb to their disease. A trial testing the combination of lurbinectedin and doxorubicin failed to improve survival compared with standard-of-care. We assessed lurbinectedin in combination with 43 other agents in SCLC cells. The top synergistic hit was the clinically relevant ATR inhibitor berzosertib which was 4-fold more synergistic than doxorubicin. Compared with lurbinectedin alone, the combination with berzosertib caused a 3.5-fold increase in DNA damage while significantly reducing the ability of cells to sense this damage by inhibiting γH2AX induction. This led to continued DNA replication even in the presence of lurbinectedin induced DNA damage, causing mitotic catastrophe and cell death. The combination was highly synergistic in 6 of 9 SCLC cell lines tested. Synergy was inversely correlated with p21 RNA and protein expression. The canonical role of p21 is to inhibit G1/S transition, and we found that thymidine induced G1 arrest inhibited synergy, while p21 knock-down increased the synergy. Interestingly, we observed synergy was inversely correlated with NE differentiation. In a high NE high p21 mouse model of SCLC, lurbinectedin alone was highly effective, with the combination showing little improvement. Conversely in a non-NE low p21 mouse model, lurbinectedin treatment alone was less effective, however the addition of berzosertib was synergistic and significantly improved efficacy. Overall, this work demonstrated berzosertib augments lurbinectedin efficacy in the recalcitrant non-NE SCLC subsets, and supported the development of a clinical trial testing lurbinectedin and berzosertib in SCLC patients NCT04802174. Citation Format: Christopher William Schultz, Yang Zhang, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Devon Atkinson, Liton Saha, Brian Elenbaas, Chien-Fei Lee, Astrid Zimmerman, Thomas Ried, Frank Zenke, Zoe Weaver, Rajaa Elmeskini, Yves Pommier, Anish Thomas. ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2153.
Abstract 4124: Clinical outcomes in women with metastatic HER2-Low breast cancer in the real world
Authors: Changchuan Jiang, Stuthi Perimbeti, Lei Deng, Charles L. Shapiro, Shipra Gandhi
Journal: Cancer Research (2022)

Abstract Background: The development of novel anti-HER2 drugs opens new treatment options for patients with breast cancers, including women with lower expression of HER2. The aim of this study was to compare the clinical outcomes of HER2-low and HER2-zero metastatic breast cancer in the real world. Methods: Female patients diagnosed with metastatic breast cancer and low HER2 expression or HER2-zero expression between 2010 and 2017, and who received systematic therapy, were identified from the National Cancer Database (NCDB). The National Cancer Data Base (NCDB) is a nationwide oncology outcomes database that collects information on approximately 70% of all new invasive cancer diagnoses in the United States.HER2-Low was defined as IHC1+ or 2+/ISH negative, whereas HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guideline. The primary outcome was overall survival(OS). A multivariable Cox regression model was performed to estimate hazard ratios (HR), adjusting for age, race/ethnicity, education, comorbidities, grade, presence of visceral metastasis, and the type of cancer center where patients were treated. The analyses were stratified by hormone receptor status. Results: A total of 22817 of 33417 (68%) were HER2-low and 10600 (32%) were HER2-zero. Hormone receptor-positivity was in 19988 (88%) with HER2-low tumors, whereas 8112 (77%) was in HER2-zero tumors. Women with HER2-low tumors had significantly longer overall survival (OS) than did with Her2-zero tumors in both hormone receptor-positive (median OS 39.0 months vs 37.1 months; adjusted HR: 0.93, 95%CI (0.90-0.96), p&amp;lt;0.001) and hormone receptor-negative groups (median OS 15.8 months vs 14.1 months; adjusted HR: 0.92 95%CI (0.86-0.98), p=0.005). Conclusion: In the metastatic setting, HER2-low tumors have a better survival than HER2-zero tumors, irrespective of hormone receptor status. Specific therapies, such as trastuzmab deruxtecan, have activity in women with HER-low breast cancers and additional therapeutics for HER-2 low should be sought. Citation Format: Changchuan Jiang, Stuthi Perimbeti, Lei Deng, Charles L. Shapiro, Shipra Gandhi. Clinical outcomes in women with metastatic HER2-Low breast cancer in the real world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4124.
Abstract 4011: Prognostic value of transcriptomic analysis in residual post neo-adjuvant triple negative breast cancer tumors
Authors: Adriana Aguilar-Mahecha, Yasamin Majedi, Oluwadara Elebute, Josiane Lafleur, Andreas Papadakis, Cathy Lan, Manuela Pelmus, Touhidur Rashid, Sarah Jenna, Mark Basik
Journal: Cancer Research (2022)

Abstract Background: Triple negative breast cancer is the most aggressive type of breast cancer. Approximately 50% of TNBC patients respond to pre-operative neo-adjuvant chemotherapy (NAC), however those patients with residual disease (non-pathological complete response or non-pCR) have a very poor prognosis. Recently, the use of capecitabine in the adjuvant setting was shown to increase disease-free survival in non-pCR patients. However, there are no biomarkers to identify patients who may benefit from adjuvant capecitabine. Moreover, novel therapeutic targets are needed to treat patients with non-pCR. Methods: RNA extracted from 32 Formalin Fixed Paraffin Embedded (FFPE) residual post-NAC tumor samples underwent NanoString nCounter gene expression analysis using the BC360 panel as well as RNAseq. Results: Comparison of tumors from poor (RFS&amp;lt;2 yrs) and good prognosis (RFS&amp;gt;2 yrs) patients showed 65 genes differentially expressed (≥1.5 fold change and p&amp;lt;0.05) by nCounter. 40 of these genes had differential expression also validated by RNAseq (R2= 0.96) and were selected for further pathway analysis. Gene Set Enrichment Analysis (GSEA) showed an enrichment for biological pathways involved in cell cycle, with all genes in this set upregulated in the poor prognosis group. GSEA analysis of 310 upregulated genes identified by RNAseq showed an enrichment for biological pathways associated with cell population proliferation and skin development. Interestingly, one of the upregulated genes identified was TYMS, encoding thymidylate synthase, the target of capecitabine, which showed 2-fold increased expression in the poor prognosis group (p≤0.005). Conclusion: Our results suggest that residual tumors from TNBC patients who relapse within two years of surgery show transcriptomic evidence of increased proliferation and that expression levels of TYMS may be a potential biomarker to select patients for capecitabine in the adjuvant setting. Citation Format: Adriana Aguilar-Mahecha, Yasamin Majedi, Oluwadara Elebute, Josiane Lafleur, Andreas Papadakis, Cathy Lan, Manuela Pelmus, Touhidur Rashid, Sarah Jenna, Mark Basik. Prognostic value of transcriptomic analysis in residual post neo-adjuvant triple negative breast cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4011.